It is known for long that the tumor tissue consists of heterogeneous cell populations with different functions and morphologies. The tumor/cancer stem cells (TSC/CSC) hypothesis supposes that the tumor is formed via progressive proliferation and differentiation of tumor stem cells, which is similar to normal tissues and organs, leading to heterogeneity. The tumor stem cells, which are named for having properties similar to normal stem cells, refer to a group of cells that have a relatively low content in tumor tissues, infinite self-renewal ability and the ability of initiating tumor formation and growth. However, it does not mean that TSCs are definitely derived from corresponding normal stem cells or necessarily associated with normal stem cells. With this consideration, these cells are also called as tumor initiating cells (TIC) or tumor propagating cells (TPC) to avoid misunderstanding. Tumor stem cells exhibit strong tumorigenicity/carcinogenicity in animals (100 such cells, or even several such cells, may induce formation of tumor/cancer in immunodeficient mice), strong drug resistance and invasive growth. These cells also have a potential of differentiating into cells that are not tumorigenic. The presence of these tumor stem cells is regarded as the substantial cause of tumor generation, tumor development and treatment failure.
Since the tumor stem cells were isolated and identified from blood for the first time, tumor stem cells have been proved to be present in solid tumors such as brain cancer, breast cancer, prostatic cancer and colon cancer. Regarding liver cancer, several research groups employed different strategies and also found liver cancer stem cells derived from cultured cell lines or clinical specimens. For example, the side population (SP) cells isolated from Huh7 cells could induce tumors by animal experiments through continuous inoculation. Also, it is reported that CD133 can be used as a marker of liver cancer stem cells in Huh7 and PLC8024 cell lines. Recently, CD90, EpCAM, OV6, CD133/ALDH were also successfully used in separation of liver cancer stem cells. Although tumor cells with stem cell-like properties have been identified through different ways, various types of cells separated from tumors of different origins with a same marker differ greatly in biological properties as the already discovered markers of tumor stem cells did not exhibit a good specificity. In this regard, whether the tumor stem cells exist or not and what the tumor stem cells are in nature are being discussed. Actually, the term ‘tumor stem cell’ or ‘tumor initiating cell’, or even ‘tumor propagating cell’ is only an operational term, the nature of which needs to be further looked into. Nevertheless, a common conclusion is that, there are a group of cells in tumor tissues which are resistant to radiotherapy and chemotherapy and have strong tumorigenicity in immunodeficient animals. Whatever they are named as, they are the primary causes of treatment failure and tumor recurrence. Separation and identification of these cells provides a new idea to the diagnosis and treatment of tumors. Treatment in the past was mainly focused on low malignant cells which existed in a large quantity in the tumor popularity. However, the tumor initiating cells, despite of low percentage, would survive and gradually grow and transfer to other sites due to resistance to conventional radiotherapy and chemotherapy, leading to the recurrence and metastasis of tumors. In this regard, the drugs directed to eliminate tumor initiating cells can fundamentally prevent the tumors from recurring and metastasizing. These drugs, being alone or in combination with conventional surgeries, radiotherapy or chemotherapy will be the beginning of a new dawn for curing tumor completely. These tumor initiating cells should be treated as targets for tumor diagnosis, treatment and prognosis.
Recently, great progress has been achieved in experiments on tumor treatment by targeting the tumor stem cells. For example, in the colorectal cancer, the CD133-positive tumor stem cells express a high level of IL-4 and thus inhibit apoptosis, and thus, treating the CD133-positive tumor stem cells with inhibitors of IL-4 makes them more sensitive to drugs. Researches also indicated that the use of anti-CD44 antibody may eliminate the tumor stem cells in acute leucocythemia so as to cure such conditions.
The development of drugs against tumor stem cells may aim at key molecules in the signaling pathways involved in self-renewal, drug resistance or invasive growth of tumor stem cells. The drug development may also focus on markers located on the cell surface as well as the niches where the cells exist and live. Molecules involved in these key processes are found based on the isolation and identification of tumor stem cells and deep understanding of the nature of malignant biological properties as well as the underlying mechanism of regulation. It should be noted that, compared to the commonly mentioned tumor related antigens, molecules related to the tumor stem cells are usually expressed in a relatively low level. Thus, the discovery of these molecules is mainly based on the specific expression but not over-expression of these molecules in tumor stem cell-like populations.
With the current drug development technology advancing, a specific antagonist can be designed with respect to a specific molecule using computer simulation, and candidate drugs can be screened from existing libraries of lead drugs. Also, an antibody with antagonism effect can be prepared and target drugs can be screened out by using other molecular and cellular biotechnologies such as the phage display method.
Monoclonal antibody technology has been used as a conventional technology to prepare antibodies that targets specific antigens or particular cells. Many antibodies have been used directly or through modification via genetic engineering into chimeric mouse-human antibodies or even completely humanized antibodies to treat several clinical diseases such as therioma. So far, the experiments concerning the antibody-mediated tumor stein cell-targeted treatments involve CD44, p-glycoprotein 1, hyaluronan receptor, EpCAM, CD326, CXCR4, IL-4, DLL4, ALDH and etc.
A marker that may be used to specifically identify tumor initiating cells is needed in this field to screen and identify such cells. Furthermore, the marker can be used in the clinical diagnosis and prognosis. The marker can also be used in the study on the malignant biological behaviors of these cells and the molecular mechanism of regulation. In the meanwhile, drugs directed at the tumor initiating cells may be developed so as to treat tumors and prevent the tumors from recurring and metastasizing fundamentally.